Enzyme targets for drug design of new anti-virulence therapeutics

Curr Opin Struct Biol. 2018 Dec;53:140-150. doi: 10.1016/j.sbi.2018.08.010. Epub 2018 Sep 14.

Abstract

Society has benefitted greatly from the use of antibiotics. Unfortunately, the misuse of these valuable molecules has resulted in increased levels of antibiotic resistance, a major global and public health issue. This resistance and the reliance on a small number of biological targets for the development of antibiotics emphasizes the need for new targets. A critical aspect guiding the development of new antimicrobials through a rational structure-guided approach is to understand the molecular structures of specific biological targets of interest. Here we give an overview of the structures of bacterial virulence enzyme targets involved in protein folding, peptidoglycan biosynthesis and cell wall modification. These include enzymes of the thiol-disulphide oxidoreductase pathway (DSB enzymes), peptidyl-proly cis/trans isomerases (Mips), enzymes from the Mur pathway and enzymes involved in lipopolysaccharide modification (EptA and ArnT). We also present progress towards inhibitor design of these targets for the development of novel anti-virulence therapeutic agents.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacteria* / enzymology
  • Bacteria* / metabolism
  • Bacterial Infections / drug therapy
  • Bacterial Proteins* / chemistry
  • Bacterial Proteins* / metabolism
  • Drug Design
  • Hexosyltransferases / metabolism
  • Humans
  • Peptidylprolyl Isomerase / chemistry
  • Peptidylprolyl Isomerase / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / chemistry
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein Disulfide Reductase (Glutathione) / chemistry
  • Protein Disulfide Reductase (Glutathione) / metabolism
  • Protein Domains
  • Protein Structure, Quaternary
  • Virulence Factors* / chemistry
  • Virulence Factors* / metabolism

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Virulence Factors
  • Protein Disulfide Reductase (Glutathione)
  • Hexosyltransferases
  • Phosphotransferases (Alcohol Group Acceptor)
  • Peptidylprolyl Isomerase